Project Summary/Abstract This R01 proposal, ?Leveraging Existing Aging Research Networks to investigate Traumatic Brain Injury (TBI) and Alzheimer?s Disease (AD) and AD related dementia (ADRD) risk? (LEARN TBI & AD), is in response to PAR 17-088 which requests secondary analyses of existing data resources to address clinical aging research questions. In this interdisciplinary project, we will use existing and newly collected data from 5 of the largest NIH-funded studies of aging (Adult Change in Thought Study, Religious Orders Study, Memory and Aging Project, Minority Aging Research Study, and Framingham Heart Study), to examine the association of TBI and repetitive head impacts (RHI) with AD/ADRD. Decades of research on the relationship between head trauma and dementia remain inconclusive; studies have reported contradictory findings but differences in methods and measurements preclude direct comparisons. Individual studies are limited by sample size and insufficient demographic diversity, so complex models of effect modification and subgroup differences in AD/ADRD risk have not been possible. In this proposal, we will use data from >19,700 individuals across 5 studies with up to 24 years of longitudinal clinical data and autopsy endpoints to definitively characterize the associations of TBI/RHI and AD/ADRD in the community. We will use advanced psychometric methods to harmonize key variables across cohorts and conduct integrative or coordinated analyses of individual patient data from all 5 studies. In Aim 1, we will test the association of TBI with clinically diagnosed dementia, including AD and other common neurodegenerative conditions such as dementia with Lewy bodies (DLB) and Parkinson?s disease (PD). We also will evaluate common AD/ADRD endophenotypes including cognition, activities of daily living (ADLs), mood and motor function, and chronic disease comorbidity. In Aim 2, we will use neuropathological data from all 5 autopsy cohorts to test the association of TBI with pathologically confirmed AD, LBD, PD, and other ADRDs. We will also consider semi-quantitative and quantitative pathological endpoints that have been implicated as dementia-related neuropathology including measures of neurofibrillary tangles, diffuse and neuritic plaques, Lewy bodies, TDP-43 and vascular pathology. In both Aims 1 and 2, we will determine whether genetic risk loci associated with brain function and disease modify these associations. In Aim 3, we will determine the frequency of chronic traumatic encephalopathy (CTE) neuropathology, defined by consensus-derived diagnostic criteria, in the community. To date, research on CTE has been limited to highly selected cohorts of athletes, and little is known about the presence of CTE pathology or its relevance to AD/ADRD clinical outcomes in community-based settings. The proposed project stands to significantly advance scientific understanding of the complex associations of TBI/RHI and AD/ADRD. By leveraging data from multiple diverse cohort studies with extensive phenotypic data, results of this study will inform strategies for prevention, intervention development, and morbidity abatement for AD/ADRD.